GU Cancers 2021 | Biomarker analysis of olaparib with or without cediranib in mCRPC
Rana McKay, MD, University of California San Diego, San Diego, CA, outlines the results of a biomarker analysis from a randomized Phase II study of olaparib with or without cediranib, an oral VEGFR tyrosine kinase inhibitor, in patients with metastatic castration-resistant prostate cancer (mCRPC). The study found that olaparib plus cediranib treatment resulted in a significantly improved radiographic progression-free survival (rPFS) in comparison to olaparib therapy alone. Biomarker analysis indicates that this benefit is likely driven by homologous recombination deficiency. This interview took place during the 2021 Genitourinary Cancers Symposium.
Transcript (edited for clarity)
So, we know that the treatment landscape for metastatic CRPC has been rapidly evolving, but despite the new treatments that have been approved for this disease, CRPC remains a lethal disease. Over the last year, we have seen PARP inhibition, PARP inhibitors be approved for use in the clinic, both olaparib and rucaparib, based on the results of the PROfound trial and the TRITON2 trial respectively...
So, we know that the treatment landscape for metastatic CRPC has been rapidly evolving, but despite the new treatments that have been approved for this disease, CRPC remains a lethal disease. Over the last year, we have seen PARP inhibition, PARP inhibitors be approved for use in the clinic, both olaparib and rucaparib, based on the results of the PROfound trial and the TRITON2 trial respectively. We know that rates of DNA damage repair gene alterations are on the order of anywhere from 20 to 30% of patients who have metastatic CRPC.
Cediranib is an oral ATP competitive tyrosine kinase inhibitor of the VEGF receptors one through three, and anti-angiogenic agents have been shown to induce a hypoxic tumor environment resulting in downregulation of homologous recombination genes, and both preclinical and clinical studies have demonstrated anti-tumor activity of the combination of cediranib plus olaparib, which really led to the hypothesis of our study, which was to look at the combination of cediranib plus olaparib compared to olaparib alone, and whether that would improve radiographic progression-free survival in men with metastatic CRPC independent of homologous recombination repair gene status.
So the study design was patients with progressive metastatic CRPC by Prostate Cancer Working Group 3 criteria who had received at least one line of prior therapy for metastatic CRPC with a good performance status of zero to one, were randomized one-to-one to receive cediranib plus olaparib versus olaparib alone with a primary endpoint of radiographic progression-free survival. The primary endpoint analyses were previously presented GU ASCO last year, and in this data set we actually present the rPFS by somatic and germline HRD status, utilizing baseline tumor biopsy.
The study did allow for crossover, and there was a mandatory baseline biopsy that was conducted in all patients. In total, 90 patients were enrolled onto the study, 45 in each arm, and we had 12 patients in arm A of cediranib and olaparib that were homologous recombination deficient, and 14 patients in arm B of olaparib alone that were homologous recombination deficient. The median follow-up for the study was 10.9 months.
The disease arms were pretty well balanced, but this was a heavily pretreated patient population. About 70% of patients had measurable disease. Over 75% of patients had received prior abiraterone. About 50% of patients had received prior enzalutamide. About 70% on that order had received prior docetaxel. So, definitely a very heavily pretreated patient population. In total 31% of evaluable patients had homologous recombination deficiency or were categorized as such. Again, 29% in the HRD, 29% with HRD in the cediranib-olaparib arm, those 12 patients we discussed, and 33%, the 14 patients in the olaparib alone arm. There were six patients that had germline alterations in homologous recombination genes.
The trial was a positive trial, demonstrating an improvement of radiographic progression-free survival with the combination compared to olaparib alone, with a PFS of 8.47 compared to 3.97, which was statistically significant. And when we did do the subset analysis by homologous recombination gene status, which was a key secondary endpoint, there was a signal that rPFS was improved with the combination of cediranib plus olaparib compared to olaparib alone in HR-deficient tumors, though the number of patients per arm was low. This trend was not really observed in the homologous recombination proficient tumors that were analyzed. We did see PSA responses and objective responses, and with regards to toxicity, the combination regimen did have increased toxicity as would be expected over the single agent of olaparib alone. But most of the grade three toxicities were limited to hypertension that was well-managed with oral medications.
So really, I think the take home message from this trial is that we demonstrate that one, cediranib plus olaparib resulted in improved radiographic progression-free survival in patients with metastatic CRPC. We were able to feasibly conduct metastasis biopsies in 93% of patients to evaluate for homologous recombination gene status. We saw that pathogenic homologous recombination deficiency alterations were seen in about 30% of patients in our study. And there was a trend for improved rPFS in patients with homologous recombination deficiency with the combination compared to olaparib alone. I think when we looked at exploratory analyses by gene status, we did see some responses across BRCA2, CDK12, and ATM genes, and I think this data does warrant further investigation of the combination of cediranib plus olaparib in patients with homologous recombination deficient metastatic CRPC.
Rana McKay, MD, has received research funding from Bayer, Pfizer and Tempus; serves on advisory boards for AstraZeneca, Bayer, Bristol Myers Squibb, Calithera, Exelixis, Janssen, Merck, Novartis, Pfizer, Sanofi and Tempus; is a consultant for Dendreon and Vividion; and serves on the molecular tumor board at Caris.